Ionizing Radiation is a cancer causing agent in man. Humans are increasingly exposed to low levels of ionizing radiation in the enrivonment through diagnostic tests, nuclear medicine procedures, and work in nuclear power industry. We propose to investigate the action of low to moderate doses of gamma (Gamma) rays and fast neutrons on human skin fibroblasts (SF) with different genetic susceptibility. These studies will be carried out on SF isolated from biopsies of normal-appearing skin taken from individuals with hereditary adenomatosis of the colon and rectum (ACR) an autosomal dominant trait. We have previously demonstrated the occurrence in these SF of abnormal phenotypic expressions which often occur in the transformed phenotype. This suggests that the ACR cells exist in an initiated state due to a dominant mutation. They were also susceptible to further transformation by oncogenic viruses, tumor promoter, carcinogen and Gamma irradiation. Presumably genetic information within ACR cells, probably in the form of a relatively limited number of DNA sequences associated with the ACR mutation, renders them more sensitive to these distinct classes of carcinogens. An experimental design that permits analysis of radiation-induced transformation as a single or as a two stage process will be applied to normal and ACR cells (1). An evaluation at this level should help to understand the quality and quantity of susceptibility mechanisms to radiation-induced alterations in human cells of distinct oncogenetic backgrounds. In these studies, cell survival and cell transformation will be investigated. The ultimate goal will be to determine the frequency of irradiation-induced transformation per viable cell. Several samples of SF representing a number of idividuals in groups with different genetic susceptibilities to cancer will be used to determine the extent of heterogeneity for normal and ACR. We feel that irradiation-induced perturbation of normal and mutant cells showing different genetic susceptibility to cancer would provide considerable insight about carcinogenic mechanisms in humans.